Endometrial cancer is the most frequent malignancy of the female genital tract and the eighth most common cause of cancer-related deaths of women in the United States. Endometrial carcinoma is broadly categorized into two major types, referred to as Type I and Type II. Type I tumors are the most common type of endometrial carcinoma and account for approximately 85% of cases. In contrast, Type II tumors are high-grade, aggressive tumors and women with this disease often have metastases at the time of presentation. Despite their low incidence, their aggressive behavior results in a disproportionate number of deaths due to endometrial carcinoma, with a five-year survival of only 10-30%. The most common molecular genetic alterations in UEC are mutations of the PTEN tumor suppressor gene and the PIK3CA oncogene. Although the main function of the protein products of both genes is regulation of the PI3K/AKT/PTEN pathway, a key pathway in controlling many aspects of cell proliferation and cell growth, we have recently shown that mutations in PTEN are present in CAH and UEC, whereas PIK3CA mutations are largely confined to UEC. Furthermore, estrogen and its primary receptor in the endometrium, ER, stimulate endometrial proliferation via activation of the PI3K/AKT/PTEN pathway. The morphologic prototype of Type II tumors is uterine serous carcinoma (USC) a high-grade tumor that occurs largely in postmenopausal women. It most commonly arises in the background of endometrial atrophy due to a lack of estrogen in the postmenopausal setting. A precursor lesion has been identified, called endometrial intraepithelial carcinoma (EIC). It consists of cells morphologically identical to those of USC, that are confined to the epithelial surfaces, without identifiable invasion. Due to the aggressive nature of the tumor, women with EIC or USC on endometrial sampling, undergo total abdominal hysterectomy and complete staging. Currently, there are no effective screening modalities for detecting early stage disease. And, like for UEC, adjuvant therapy does not change the long-term survival of women with USC. The overarching hypothesis of this application is that deregulation of PI3K/AKT/PTEN pathway by PTEN and PIK3CA mutations and estrogen/ER abnormalities are central to the development of endometrial carcinoma. The proposed set of experiments, using genetically based mouse models and primary human tumors, will define the role of the most common genetic alterations and their relationship to hormones on the development of endometrial carcinoma. These studies will increase our basic understanding of the disease, provide novel biomarkers for diagnosis, and create animal models for the future development of novel therapeutic approaches to this common disease. PUBLIC HEALTH RELEVANCE: Endometrial carcinoma, the most common malignancy of the female genital tract, causes significant mortality and morbidity in the United States. The experiments proposed in this application will result in novel diagnostic tools and create genetic mouse models that faithfully emulate the human disease that can be used to develop novel treatments for this common cancer.